G protein–coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation‐induced sensitization to excitotoxic neurodegeneration. Issue 5 (14th March 2013)

• Record Type: Journal Article
• Authors: Degos, Vincent; Peineau, Stéphane; Nijboer, Cora; Kaindl, Angela M.; Sigaut, Stéphanie; Favrais, Géraldine; Plaisant, Frank; Teissier, Natacha; Gouadon, Elodie; Lombet, Alain; Saliba, Elie; Collingridge, Graham L.; Maze, Mervyn; Nicoletti, Ferdinando; Heijnen, Cobi; Mantz, Jean; Kavelaars, Annemieke; Gressens, Pierre
• Is Part Of: Annals of neurology. Volume 73:Issue 5(2013:May)
• Page Start: 667
• Page End: 678
• Publication Date: 2013-03-14
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.23868
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana23868-sec-0001" sec-type="section"> <title>Objective</title> <p>The concept of inflammation‐induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease, and multiple sclerosis. However, mechanisms underpinning this process remain unidentified.</p> </sec> <sec id="ana23868-sec-0002" sec-type="section"> <title>Methods</title> <p>We combined in vivo systemic lipopolysaccharide‐induced or interleukin (IL)−1β–induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL‐1β sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation‐induced sensitization models, we assessed metabotropic glutamate receptors (mGluR) signaling and regulation.</p> </sec> <sec id="ana23868-sec-0003" sec-type="section"> <title>Results</title> <p>We demonstrate for the first time that group I mGluRs mediate inflammation‐induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation‐induced G protein–coupled receptor kinase 2 (GRK2) downregulation and genetic deletion of <italic>GRK2</italic> mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR‐mediated sensitization.</p> </sec> <sec id="ana23868-sec-0004" sec-type="section"> <title>Interpretation</title> <p>Collectively, our findings indicate that inflammation‐induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders. Ann Neurol 2013;73:667–678</p> </sec> </abstract>